Publications by authors named "Wes Onland"

45 Publications

Factors Associated With Benefit of Treatment of Patent Ductus Arteriosus in Preterm Infants: A Systematic Review and Meta-Analysis.

Front Pediatr 2021 9;9:626262. Epub 2021 Feb 9.

Radboud University Medical Center Nijmegen, Radboud Institute for Health Sciences, Amalia Children's Hospital, Nijmegen, Netherlands.

There is an ongoing debate on the optimal management of patent ductus arteriosus (PDA) in preterm infants. Identifying subgroup of infants who would benefit from pharmacological treatment might help. To investigate the modulating effect of the differences in methodological quality, the rate of open-label treatment, and patient characteristics on relevant outcome measures in randomized controlled trials (RCTs). Electronic database search between 1950 and May 2020. RCTs that assessed pharmacological treatment compared to placebo/no treatment. Data is extracted following the PRISMA guidelines. Outcome measures were failure to ductal closure, surgical ligation, incidence of necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, periventricular leukomalacia, intraventricular hemorrhage (IVH) grade ≥3, retinopathy of prematurity and mortality. Forty-seven studies were eligible. The incidence of IVH grade ≥3 was lower in the treated infants compared to the placebo/no treatment (RR 0.77, 95% CI 0.64-0.94) and in the subgroups of infants with either a gestational age <28 weeks (RR 0.77, 95% CI 0.61-0.98), a birth weight <1,000 g (RR 0.77, 95% CI 0.61-0.97), or if untargeted treatment with indomethacin was started <24 h after birth (RR 0.70, 95% CI 0.54-0.90). Statistical heterogeneity caused by missing data and variable definitions of outcome parameters. Although the quality of evidence is low, this meta-analysis suggests that pharmacological treatment of PDA reduces severe IVH in extremely preterm, extremely low birth weight infants or if treatment with indomethacin was started <24 h after birth. No other beneficial effects of pharmacological treatment were found.
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http://dx.doi.org/10.3389/fped.2021.626262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899974PMC
February 2021

The association between clinical and biochemical characteristics of late-onset sepsis and bronchopulmonary dysplasia in preterm infants.

Eur J Pediatr 2021 Feb 25. Epub 2021 Feb 25.

Department of Neonatology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Studies in preterm infants have shown an association between late-onset sepsis (LOS) and the development of bronchopulmonary dysplasia (BPD). It is unknown whether clinical or biochemical characteristics during sepsis modulate the risk for BPD. This single-center retrospective cohort study included all patients with a gestational age < 30 weeks, born between 2009 and 2015, in whom empiric antimicrobial treatment was initiated > 72 h after birth and continued for at least 5 days, independent on microbiological results. The association between clinical and biochemical characteristics of LOS and the development of BPD in survivors were assessed with multivariate logistic regression analysis adjusted for early-onset sepsis, small for gestational age, and gestational age. Of the 756 admitted infants, 256 infants (mean GA: 27.0 weeks; birthweight: 924 grams) had at least one LOS episode, of whom 79 (30.9%) developed BPD. Analyses showed that only the need for and duration of mechanical ventilation during LOS were independently associated with an increased risk for BPD (adjusted OR 2.62, 95% CI 1.38, 4.96, p value 0.003, and OR 1.004, 95% CI 1.00, 1.007, p value 0.045, respectively).Conclusion: During a LOS, the need for and duration of mechanical ventilation are independently associated with the risk of developing BPD in preterm infants. What is Known: • Premature infants diagnosed with a late-onset sepsis are at higher risk of developing bronchopulmonary dysplasia • This association is mainly shown in infants with a positive blood culture What is New: • This study investigates the clinical and biochemical characteristics of late-onset sepsis and the development of bronchopulmonary dysplasia • The need for mechanical ventilation and duration of mechanical ventilation during late-onset sepsis are associated with an increased risk of developing bronchopulmonary dysplasia.
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http://dx.doi.org/10.1007/s00431-021-03981-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904512PMC
February 2021

Precision Medicine in Neonates: Future Perspectives for the Lung.

Front Pediatr 2020 30;8:586061. Epub 2020 Oct 30.

Department of Neonatology, Amsterdam University Medical Centers, VU University Medical Center, Emma Children's Hospital, University of Amsterdam, Amsterdam, Netherlands.

Bronchopulmonary dysplasia (BPD) is the most common complication of pre-term birth with long lasting sequelae. Since its first description more than 50 years ago, many large randomized controlled trials have been conducted, aiming to improve evidence-based knowledge on the optimal strategies to prevent and treat BPD. However, most of these intervention studies have been performed on a population level without regard for the variation in clinical and biological diversity (e.g., gestational age, ethnicity, gender, or disease progression) between patients that is driven by the complex interaction of genetic pre-disposition and environmental exposures. Nevertheless, clinicians provide daily care such as lung protective interventions on an individual basis every day despite the fact that research supporting individualized or precision medicine for monitoring or treating pre-term lungs is immature. This narrative review summarizes four potential developments in pulmonary research that might facilitate the process of individualizing lung protective interventions to prevent development of BPD. Electrical impedance tomography and electromyography of the diaphragm are bedside monitoring tools to assess regional changes in lung volume and ventilation and spontaneous breathing effort, respectively. These non-invasive tools allow a more individualized optimization of invasive and non-invasive respiratory support. Investigation of the genomic variation in caffeine metabolism in pre-term infants can be used to optimize and individualize caffeine dosing regimens. Finally, volatile organic compound analysis in exhaled breath might accurately predict BPD at an early stage of the disease, enabling clinicians to initiate preventive strategies for BPD on an individual basis. Before these suggested diagnostic or monitoring tools can be implemented in daily practice and improve individualized patient care, future research should address and overcome their technical difficulties, perform extensive external validation and show their additional value in preventing BPD.
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http://dx.doi.org/10.3389/fped.2020.586061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673376PMC
October 2020

Maternal Docosahexaenoic Acid Supplementation and Bronchopulmonary Dysplasia in Infants.

JAMA 2020 11;324(20):2104-2105

Neonatology, Amsterdam UMC, Amsterdam, the Netherlands.

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http://dx.doi.org/10.1001/jama.2020.19404DOI Listing
November 2020

Survival and causes of death in extremely preterm infants in the Netherlands.

Arch Dis Child Fetal Neonatal Ed 2020 11 6. Epub 2020 Nov 6.

Department of Neonatology, Máxima Medical Centre, Veldhoven, The Netherlands.

Objective: In the Netherlands, the threshold for offering active treatment for spontaneous birth was lowered from 25 to 24 weeks' gestation in 2010. This study aimed to evaluate the impact of guideline implementation on survival and causes and timing of death in the years following implementation.

Design: National cohort study, using data from the Netherlands Perinatal Registry.

Patients: The study population included all 3312 stillborn and live born infants with a gestational age (GA) between 24 and 26 weeks born between January 2011 and December 2017. Infants with the same GA born between January 2007 and December 2009 (N=1400) were used as the reference group.

Main Outcome Measures: Survival to discharge, as well as cause and timing of death.

Results: After guideline implementation, there was a significant increase in neonatal intensive care unit (NICU) admission rate for live born infants born at 24 weeks' GA (27%-69%, p<0.001), resulting in increased survival to discharge in 24-week live born infants (13%-34%, p<0.001). Top three causes of in-hospital mortality were necrotising enterocolitis (28%), respiratory distress syndrome (19%) and intraventricular haemorrhage (17%). A significant decrease in cause of death either complicated or caused by respiratory insufficiency was seen over time (34% in 2011-2014 to 23% in 2015-2017, p=0.006).

Conclusions: Implementation of the 2010 guideline resulted as expected in increased NICU admissions rate and postnatal survival of infants born at 24 weeks' GA. In the years after implementation, a shift in cause of death was seen from respiratory insufficiency towards necrotising enterocolitis and sepsis.
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http://dx.doi.org/10.1136/archdischild-2020-318978DOI Listing
November 2020

Increase in treatment of retinopathy of prematurity in the Netherlands from 2010 to 2017.

Acta Ophthalmol 2021 Feb 23;99(1):97-103. Epub 2020 Jul 23.

Leiden University Medical Center, Leiden, Netherlands.

Purpose: Compare patients treated for Retinopathy of Prematurity (ROP) in two consecutive periods.

Methods: Retrospective inventory of anonymized neonatal and ophthalmological data of all patients treated for ROP from 2010 to 2017 in the Netherlands, subdivided in period (P)1: 1-1-2010 to 31-3-2013 and P2: 1-4-2013 to 31-12-2016. Treatment characteristics, adherence to early treatment for ROP (ETROP) criteria, outcome of treatment and changes in neonatal parameters and policy of care were compared.

Results: Overall 196 infants were included, 57 infants (113 eyes) in P1 and 139 (275 eyes) in P2, indicating a 2.1-fold increase in ROP treatment. No differences were found in mean gestational age (GA) (25.9 ± 1.7 versus 26.0 ± 1.7 weeks, p = 0.711), mean birth weight (791 ± 311 versus 764 ± 204 grams, p = 0.967) and other neonatal risk factors for ROP. In P2, the number of premature infants born <25 weeks increased by factor 1.23 and higher oxygen saturation levels were aimed at in most centres. At treatment decision, 59.6% (P1) versus 83.5% (P2) (p = 0.263) infants were classified as Type 1 ROP (ETROP classification). Infants were treated with laser photocoagulation (98 versus 96%) and intravitreal bevacizumab (2 versus 4%). Retreatment was necessary in 10 versus 21 (p = 0.160). Retinal detachment developed in 6 versus 13 infants (p = 0.791) of which 2 versus 6 bilateral (p = 0.599).

Conclusion: In period 2, the number of infants treated according to the ETROP criteria (Type 1) increased, the number of ROP treatments, retinal detachments and retreatments doubled and the absolute number of retinal detachments increased. Neonatal data did not provide a decisive explanation, although changes in neonatal policy were reported.
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http://dx.doi.org/10.1111/aos.14501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891652PMC
February 2021

Maternal Sildenafil vs Placebo in Pregnant Women With Severe Early-Onset Fetal Growth Restriction: A Randomized Clinical Trial.

JAMA Netw Open 2020 06 1;3(6):e205323. Epub 2020 Jun 1.

Department of Obstetrics and Gynecology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

Importance: Severe early onset fetal growth restriction caused by placental dysfunction leads to high rates of perinatal mortality and neonatal morbidity. The phosphodiesterase 5 inhibitor, sildenafil, inhibits cyclic guanosine monophosphate hydrolysis, thereby activating the effects of nitric oxide, and might improve uteroplacental function and subsequent perinatal outcomes.

Objective: To determine whether sildenafil reduces perinatal mortality or major morbidity.

Design, Setting, And Participants: This placebo-controlled randomized clinical trial was conducted at 10 tertiary referral centers and 1 general hospital in the Netherlands from January 20, 2015, to July 16, 2018. Participants included pregnant women between 20 and 30 weeks of gestation with severe fetal growth restriction, defined as fetal abdominal circumference below the third percentile or estimated fetal weight below the fifth percentile combined with Dopplers measurements outside reference ranges or a maternal hypertensive disorder. The trial was stopped early owing to safety concerns on July 19, 2018, whereas benefit on the primary outcome was unlikely. Data were analyzed from January 20, 2015, to January 18, 2019. The prespecified primary analysis was an intention-to-treat analysis including all randomized participants.

Interventions: Participants were randomized to sildenafil, 25 mg, 3 times a day vs placebo.

Main Outcomes And Measures: The primary outcome was a composite of perinatal mortality or major neonatal morbidity until hospital discharge.

Results: Out of 360 planned participants, a total of 216 pregnant women were included, with 108 women randomized to sildenafil (median gestational age at randomization, 24 weeks 5 days [interquartile range, 23 weeks 3 days to 25 weeks 5 days]; mean [SD] estimated fetal weight, 458 [160] g) and 108 women randomized to placebo (median gestational age, 25 weeks 0 days [interquartile range, 22 weeks 5 days to 26 weeks 3 days]; mean [SD] estimated fetal weight, 464 [186] g). In July 2018, the trial was halted owing to concerns that sildenafil may cause neonatal pulmonary hypertension, whereas benefit on the primary outcome was unlikely. The primary outcome, perinatal mortality or major neonatal morbidity, occurred in the offspring of 65 participants (60.2%) allocated to sildenafil vs 58 participants (54.2%) allocated to placebo (relative risk, 1.11; 95% CI, 0.88-1.40; P = .38). Pulmonary hypertension, a predefined outcome important for monitoring safety, occurred in 16 neonates (18.8%) in the sildenafil group vs 4 neonates (5.1%) in the placebo group (relative risk, 3.67; 95% CI, 1.28-10.51; P = .008).

Conclusions And Relevance: These findings suggest that antenatal maternal sildenafil administration for severe early onset fetal growth restriction did not reduce the risk of perinatal mortality or major neonatal morbidity. The results suggest that sildenafil may increase the risk of neonatal pulmonary hypertension.

Trial Registration: ClinicalTrials.gov Identifier: NCT02277132.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.5323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301225PMC
June 2020

Sustained Inflation vs Standard Resuscitation for Preterm Infants: A Systematic Review and Meta-analysis.

JAMA Pediatr 2020 Apr 6;174(4):e195897. Epub 2020 Apr 6.

Division of Biostatistics, Department of Public Health Sciences, University of Virginia, Charlottesville.

Importance: Most preterm infants require respiratory support to establish lung aeration after birth. Intermittent positive pressure ventilation and continuous positive airway pressure are standard therapies. An initial sustained inflation (inflation time >5 seconds) is a widely practiced alternative strategy.

Objective: To conduct a systematic review and meta-analysis of sustained inflation vs intermittent positive pressure ventilation and continuous positive airway pressure for the prevention of hospital mortality and morbidity for preterm infants.

Data Sources: MEDLINE (through PubMed), Embase, the Cumulative Index of Nursing and Allied Health Literature, and the Cochrane Central Register of Controlled Trials were searched through June 24, 2019.

Study Selection: Randomized clinical trials of preterm infants born at less than 37 weeks' gestation that compared sustained inflation (inflation time >5 seconds) vs standard resuscitation with either intermittent positive pressure ventilation or continuous positive airway pressure were included. Studies including other cointerventions were excluded.

Data Extraction And Synthesis: Two reviewers assessed the risk of bias of included studies. Meta-analysis of pooled outcome data used a fixed-effects model specific to rarer events. Subgroups were based on gestational age and study design (rescue vs prophylactic sustained inflation).

Main Outcomes And Measures: Death before hospital discharge.

Results: Nine studies recruiting 1406 infants met inclusion criteria. Death before hospital discharge occurred in 85 of 736 infants (11.5%) treated with sustained inflation and 62 of 670 infants (9.3%) who received standard therapy for a risk difference of 3.6% (95% CI, -0.7% to 7.9%). Although analysis of the primary outcome identified important heterogeneity based on gestational age subgroups, the 95% CI for the risk difference included 0 for each individual gestational age subgroup. There was no difference in the primary outcome between subgroups based on study design. Sustained inflation was associated with increased risk of death in the first 2 days after birth (risk difference, 3.1%; 95% CI, 0.9%-5.3%). No differences in the risk of other secondary outcomes were identified. The quality-of-evidence assessment was low owing to risk of bias and imprecision.

Conclusions And Relevance: There was no difference in the risk of the primary outcome of death before hospital discharge, and there was no evidence of efficacy for sustained inflation to prevent secondary outcomes. These findings do not support the routine use of sustained inflation for preterm infants after birth.
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http://dx.doi.org/10.1001/jamapediatrics.2019.5897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042947PMC
April 2020

Preterm neonates benefit from low prophylactic platelet transfusion threshold despite varying risk of bleeding or death.

Blood 2019 12;134(26):2354-2360

Center for Clinical Transfusion Research, Sanquin Research, Leiden, The Netherlands.

The Platelets for Neonatal Thrombocytopenia (PlaNeT-2) trial reported an unexpected overall benefit of a prophylactic platelet transfusion threshold of 25 × 109/L compared with 50 × 109/L for major bleeding and/or mortality in preterm neonates (7% absolute-risk reduction). However, some neonates in the trial may have experienced little benefit or even harm from the 25 × 109/L threshold. We wanted to assess this heterogeneity of treatment effect in the PlaNet-2 trial, to investigate whether all preterm neonates benefit from the low threshold. We developed a multivariate logistic regression model in the PlaNet-2 data to predict baseline risk of major bleeding and/or mortality for all 653 neonates. We then ranked the neonates based on their predicted baseline risk and categorized them into 4 risk quartiles. Within these quartiles, we assessed absolute-risk difference between the 50 × 109/L- and 25 × 109/L-threshold groups. A total of 146 neonates died or developed major bleeding. The internally validated C-statistic of the model was 0.63 (95% confidence interval, 0.58-0.68). The 25 × 109/L threshold was associated with absolute-risk reduction in all risk groups, varying from 4.9% in the lowest risk group to 12.3% in the highest risk group. These results suggest that a 25 × 109/L prophylactic platelet count threshold can be adopted in all preterm neonates, irrespective of predicted baseline outcome risk. Future studies are needed to improve the predictive accuracy of the baseline risk model. This trial was registered at www.isrctn.com as #ISRCTN87736839.
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http://dx.doi.org/10.1182/blood.2019000899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933290PMC
December 2019

Sequential co-enrolment in randomised trials in neonatal intensive care medicine.

Arch Dis Child Fetal Neonatal Ed 2020 Mar 1;105(2):128-131. Epub 2019 Jun 1.

Department of Clinical Epidemiology, Leiden University Medical Centre, Leiden, the Netherlands.

In many medical research settings, such as the neonatal intensive care unit, the number of patients who are eligible for a randomised clinical trial is relatively small and recruiting a sufficient number of patients into trials is often difficult. Furthermore, some infants may have already been enrolled into a trial as a fetus. Sequential co-enrolment of patients into more than one trial may offer a solution, yet runs the risk of contaminated results. We consider the situation of two sequential trials and describe requirements for different possible treatments effects ('estimands') to be estimated in such situations. These estimands differ regarding the extent to which participation status and treatment status in the previous trial is accounted for. Because of differences in available information about previous trials, analyses may result in estimated effects which differ in terms of interpretation and generalisability, except when in the absence of an interaction between the studied treatments. If co-enrolment cannot be ruled out, researchers should collect information about co-enrolment and treatment status in a previous or concurrent trial and mitigate the trial analysis plan in order to estimate meaningful effects.
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http://dx.doi.org/10.1136/archdischild-2019-316818DOI Listing
March 2020

Minimally invasive surfactant therapy failure: risk factors and outcome.

Arch Dis Child Fetal Neonatal Ed 2019 Nov 29;104(6):F636-F642. Epub 2019 Apr 29.

Department of Neonatology, Máxima Medical Centre, Veldhoven, The Netherlands.

Objective: To evaluate incidence of minimally invasive surfactant therapy (MIST) failure, identify risk factors and assess the impact of MIST failure on neonatal outcome.

Design: Retrospective cohort study. MIST failure was defined as need for early mechanical ventilation (<72 hours of life). Multivariate logistic regression analysis was performed to identify risk factors for MIST failure and compare outcomes between groups.

Setting: Two tertiary neonatal intensive care centres in the Netherlands.

Patients: Infants born between 24 weeks' and 31 weeks' gestational age (GA) (n=185) with MIST for respiratory distress syndrome.

Interventions: MIST procedure with poractant alfa (100-200 mg/kg).

Main Outcome Measures: Continuous positive airway pressure (CPAP) failure after MIST in the first 72 hours of life.

Results: 30% of the infants failed CPAP after MIST. In a multivariate logistic regression analysis, four risk factors were independently associated with failure: GA <28 weeks, C reactive protein ≥10 mg/L, absence of antenatal corticosteroids and lower surfactant dose. Infants receiving 200 mg/kg surfactant had a failure rate of 14% versus 35% with surfactant dose <200 mg/kg. Mean body temperature was 0.4°C lower at neonatal intensive care unit admission and before the procedure in infants with MIST failure.Furthermore, MIST failure was independently associated with an increased risk of severe intraventricular haemorrhage.

Conclusion: We observed moderate MIST failure rates in concordance with the results of earlier studies. Absence of corticosteroids and lower surfactant dose are risk factors for MIST failure that may be modifiable in order to improve MIST success and patient outcome.
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http://dx.doi.org/10.1136/archdischild-2018-316258DOI Listing
November 2019

Effect of Sustained Inflations vs Intermittent Positive Pressure Ventilation on Bronchopulmonary Dysplasia or Death Among Extremely Preterm Infants: The SAIL Randomized Clinical Trial.

JAMA 2019 03;321(12):1165-1175

Department of Pediatrics, Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama, Japan.

Importance: Preterm infants must establish regular respirations at delivery. Sustained inflations may establish lung volume faster than short inflations.

Objective: To determine whether a ventilation strategy including sustained inflations, compared with standard intermittent positive pressure ventilation, reduces bronchopulmonary dysplasia (BPD) or death at 36 weeks' postmenstrual age without harm in extremely preterm infants.

Design, Setting, And Participants: Unmasked, randomized clinical trial (August 2014 to September 2017, with follow-up to February 15, 2018) conducted in 18 neonatal intensive care units in 9 countries. Preterm infants 23 to 26 weeks' gestational age requiring resuscitation with inadequate respiratory effort or bradycardia were enrolled. Planned enrollment was 600 infants. The trial was stopped after enrolling 426 infants, following a prespecified review of adverse outcomes.

Interventions: The experimental intervention was up to 2 sustained inflations at maximal peak pressure of 25 cm H2O for 15 seconds using a T-piece and mask (n = 215); standard resuscitation was intermittent positive pressure ventilation (n = 211).

Main Outcome And Measures: The primary outcome was the rate of BPD or death at 36 weeks' postmenstrual age. There were 27 prespecified secondary efficacy outcomes and 7 safety outcomes, including death at less than 48 hours.

Results: Among 460 infants randomized (mean [SD] gestational age, 25.30 [0.97] weeks; 50.2% female), 426 infants (92.6%) completed the trial. In the sustained inflation group, 137 infants (63.7%) died or survived with BPD vs 125 infants (59.2%) in the standard resuscitation group (adjusted risk difference [aRD], 4.7% [95% CI, -3.8% to 13.1%]; P = .29). Death at less than 48 hours of age occurred in 16 infants (7.4%) in the sustained inflation group vs 3 infants (1.4%) in the standard resuscitation group (aRD, 5.6% [95% CI, 2.1% to 9.1%]; P = .002). Blinded adjudication detected an imbalance of rates of early death possibly attributable to resuscitation (sustained inflation: 11/16; standard resuscitation: 1/3). Of 27 secondary efficacy outcomes assessed by 36 weeks' postmenstrual age, 26 showed no significant difference between groups.

Conclusions And Relevance: Among extremely preterm infants requiring resuscitation at birth, a ventilation strategy involving 2 sustained inflations, compared with standard intermittent positive pressure ventilation, did not reduce the risk of BPD or death at 36 weeks' postmenstrual age. These findings do not support the use of ventilation with sustained inflations among extremely preterm infants, although early termination of the trial limits definitive conclusions.

Trial Registration: clinicaltrials.gov Identifier: NCT02139800.
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http://dx.doi.org/10.1001/jama.2019.1660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439695PMC
March 2019

Duration of mechanical ventilation and neurodevelopment in preterm infants.

Arch Dis Child Fetal Neonatal Ed 2019 Nov 20;104(6):F631-F635. Epub 2019 Mar 20.

Neonatology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Objective: To investigate the association between invasive mechanical ventilation (IMV) duration and long-term neurodevelopmental outcomes in preterm infants in an era of restricted IMV.

Design: Retrospective cohort study.

Setting: Single neonatal intensive care unit in Amsterdam.

Patients: All ventilated patients with a gestational age between 24 and 30 weeks born between 2010 and 2015.

Main Outcome Measures: Neurodevelopmental impairment (NDI) at 24 months corrected age (CA). Data on patient characteristics, respiratory management, neonatal morbidities, mortality and bronchopulmonary dysplasia were collected. The relationship between IMV duration and NDI was determined by multivariate logistic regression analysis.

Results: During the study period, 368 admitted infants received IMV for a median duration of 2 days. Moderate and severe bronchopulmonary dysplasia was diagnosed in 33% of the infant. Multivariate regression analysis with adjustment for gestational age, small for gestational age and socioeconomic status showed a significant association between every day of IMV and NDI at 24 months CA (adjusted OR [aOR] 1.08, 95% CI 1.004 to 1.16, p=0.04). This association only reached borderline significance when also adjusting for severe neonatal morbidity (aOR 1.08, 95% CI 1.00 to 1.17, p=0.05).

Conclusion: Even in an era of restricted IMV, every additional day of IMV in preterm infants is strongly associated with an increased risk of NDI at 24 months CA. Limiting IMV should be an important focus in the treatment of preterm infants.
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http://dx.doi.org/10.1136/archdischild-2018-315993DOI Listing
November 2019

Dynamic prediction of bleeding risk in thrombocytopenic preterm neonates.

Haematologica 2019 11 28;104(11):2300-2306. Epub 2019 Feb 28.

Sanquin/LUMC, Center for Clinical Transfusion Research, Leiden

Over 75% of severely thrombocytopenic neonates receive platelet transfusions, though little evidence supports this practice, and only 10% develop major bleeding. In a recent randomized trial, giving platelet transfusions at a threshold platelet count of 50x10/L compared to a threshold of 25x10/L was associated with an increased risk of major bleeding or mortality. This finding highlights the need for improved and individualized guidelines on neonatal platelet transfusion, which require accurate prediction of bleeding risk. Therefore, the objective of this study was to develop a dynamic prediction model for major bleeding in thrombocytopenic preterm neonates. This model allows for calculation of bleeding risk at any time-point during the first week after the onset of severe thrombocytopenia. In this multicenter cohort study, we included neonates with a gestational age <34 weeks, admitted to a neonatal intensive care unit, who developed severe thrombocytopenia (platelet count <50x10/L). The study endpoint was major bleeding. We obtained predictions of bleeding risk using a proportional baselines landmark supermodel. Of 640 included neonates, 71 (11%) had a major bleed. We included the variables gestational age, postnatal age, intrauterine growth retardation, necrotizing enterocolitis, sepsis, platelet count and mechanical ventilation in the model. The median cross-validated c-index was 0.74 (interquartile range, 0.69-0.82). This is a promising dynamic prediction model for bleeding in this population that should be explored further in clinical studies as a potential instrument for supporting clinical decisions. The study was registered at (NCT03110887).
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http://dx.doi.org/10.3324/haematol.2018.208595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821634PMC
November 2019

Effect of Hydrocortisone Therapy Initiated 7 to 14 Days After Birth on Mortality or Bronchopulmonary Dysplasia Among Very Preterm Infants Receiving Mechanical Ventilation: A Randomized Clinical Trial.

JAMA 2019 01;321(4):354-363

Department of Neonatology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

Importance: Dexamethasone initiated after the first week of life reduces the rate of death or bronchopulmonary dysplasia (BPD) but may cause long-term adverse effects in very preterm infants. Hydrocortisone is increasingly used as an alternative, but evidence supporting its efficacy and safety is lacking.

Objective: To assess the effect of hydrocortisone initiated between 7 and 14 days after birth on death or BPD in very preterm infants.

Design, Setting, And Participants: Double-blind, placebo-controlled randomized trial conducted in 19 neonatal intensive care units in the Netherlands and Belgium from November 15, 2011, to December 23, 2016, among preterm infants with a gestational age of less than 30 weeks and/or birth weight of less than 1250 g who were ventilator dependent between 7 and 14 days of life, with follow-up to hospital discharge ending December 12, 2017.

Interventions: Infants were randomly assigned to receive a 22-day course of systemic hydrocortisone (cumulative dose, 72.5 mg/kg) (n = 182) or placebo (n = 190).

Main Outcomes And Measures: The primary outcome was a composite of death or BPD assessed at 36 weeks' postmenstrual age. Twenty-nine secondary outcomes were analyzed up to hospital discharge, including death and BPD at 36 weeks' postmenstrual age.

Results: Among 372 patients randomized (mean gestational age, 26 weeks; 55% male), 371 completed the trial; parents withdrew consent for 1 child treated with hydrocortisone. Death or BPD occurred in 128 of 181 infants (70.7%) randomized to hydrocortisone and in 140 of 190 infants (73.7%) randomized to placebo (adjusted risk difference, -3.6% [95% CI, -12.7% to 5.4%]; adjusted odds ratio, 0.87 [95% CI, 0.54-1.38]; P = .54). Of 29 secondary outcomes, 8 showed significant differences, including death at 36 weeks' postmenstrual age (15.5% with hydrocortisone vs 23.7% with placebo; risk difference, -8.2% [95% CI, -16.2% to -0.1%]; odds ratio, 0.59 [95% CI, 0.35-0.995]; P = .048). Twenty-one outcomes showed nonsignificant differences, including BPD (55.2% with hydrocortisone vs 50.0% with placebo; risk difference, 5.2% [95% CI, -4.9% to 15.2%]; odds ratio, 1.24 [95% CI, 0.82-1.86]; P = .31). Hyperglycemia requiring insulin therapy was the only adverse effect reported more often in the hydrocortisone group (18.2%) than in the placebo group (7.9%).

Conclusions And Relevance: Among mechanically ventilated very preterm infants, administration of hydrocortisone between 7 and 14 days after birth, compared with placebo, did not improve the composite outcome of death or BPD at 36 weeks' postmenstrual age. These findings do not support the use of hydrocortisone for this indication.

Trial Registration: Netherlands National Trial Register Identifier: NTR2768.
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http://dx.doi.org/10.1001/jama.2018.21443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439762PMC
January 2019

Detailed statistical analysis plan for the Dutch STRIDER (Sildenafil TheRapy In Dismal prognosis Early-onset fetal growth Restriction) randomised clinical trial on sildenafil versus placebo for pregnant women with severe early onset fetal growth restriction.

Trials 2019 Jan 11;20(1):42. Epub 2019 Jan 11.

The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Objective: The objective of the Dutch Sildenafil therapy in dismal prognosis early onset fetal growth restriction (STRIDER) randomised clinical trial is to assess the beneficial and harmful effects of sildenafil versus placebo on fetal and neonatal mortality in pregnant women with severe early-onset fetal growth restriction. The objective of this detailed statistical analysis plan is to minimize the risks of selective reporting and data-driven analysis.

Setting: The setting is 10 tertiary care hospitals and one secondary care hospital in The Netherlands.

Participants: The participants will be 360 pregnant women with severe early-onset fetal growth restriction.

Interventions: The intervention is sildenafil 25 mg or placebo orally three times a day.

Primary And Secondary Outcome Measures: The primary outcome is a composite of death or major neonatal morbidity assessed at hospital discharge. The secondary outcomes are neurodevelopmental impairment; mean scores of the Bayley III cognitive and motor assessment; the proportion of patients experiencing either preeclampsia or haemolysis, elevated liver enzymes, and low platelets syndrome; pulsatility index of uterine arteries, umbilical artery, and middle cerebral artery; birthweight; and gestational age at either delivery or intra-uterine death.

Results: A detailed statistical analysis is presented, including pre-defined exploratory outcomes and planned subgroup analyses. One interim analysis after 180 patients had completed the study was planned and a strategy to minimise the risks of type I errors due to repetitive testing is presented. During review of this manuscript the interim analysis was performed by the Data Safety Monitoring Board and early stopping of the trial was recommended. Final analyses will be conducted independently by two statistically qualified persons following the present plan.

Conclusion: This pre-specified statistical analysis plan was written and submitted without knowledge of the unblinded data and updated after stopping of the trial at interim analysis.

Trial Registration: ClinicalTrials.gov, NCT02277132 . Registered on 29 September 2014. Original protocol for the study: doi: https://doi.org/10.5281/zenodo.56148.
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http://dx.doi.org/10.1186/s13063-018-3136-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330484PMC
January 2019

High versus low dose caffeine in preterm infants.

Acta Paediatr 2019 03 9;108(3):570-571. Epub 2019 Jan 9.

Department of Neonatology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1111/apa.14651DOI Listing
March 2019

Randomized Trial of Platelet-Transfusion Thresholds in Neonates.

N Engl J Med 2019 01 2;380(3):242-251. Epub 2018 Nov 2.

From the Department of Neonatology, National Maternity Hospital, Dublin (A.C.), and University Maternity Hospital Limerick, Limerick (R.K.) - both in Ireland; Department of Transfusion Medicine, National Health Service (NHS) Blood and Transplant, the Department of Haematology, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, the Radcliffe Department of Medicine, University of Oxford, and Oxford Biomedical Research Centre Haematology Theme, Oxford (S.J.S.), the Department of Obstetrics and Gynaecology, University of Cambridge (K.W.), NHS Blood and Transplant, Clinical Trials Unit (K.W., C.H., A. Deary, R.H., V.H., A.M., C.L.), and the Neonatal Intensive Care Unit, Cambridge University Hospitals NHS Trust (A. D'Amore), Cambridge, the Neonatal Intensive Care Unit, Evelina London Children's Hospital, Guy's and St. Thomas' NHS Foundation Trust (B.L.S., T.W.), NHS Blood and Transplant (H.N.), and the Department of Hematology, Imperial College London (H.N.), London, and the Neonatal Intensive Care Unit, Norfolk and Norwich University Hospitals NHS Foundation Trust, and Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich (P.C.) - all in the United Kingdom; the Center for Clinical Transfusion Research, Sanquin Blood Supply (S.F.F.-G., K.F.), and the Departments of Epidemiology (S.F.F.-G.) and Neonatology (E.L.), Leiden University Medical Center, Leiden, and the Departments of Pediatric Hematology (S.F.F.-G., K.F.) and Neonatology (W.O.), Emma Children's Hospital, Academic Medical Center, Amsterdam - both in the Netherlands; and the Neonatal Intensive Care Unit, Cloudnine Hospital, Bangalore, India (V.V.).

Background: Platelet transfusions are commonly used to prevent bleeding in preterm infants with thrombocytopenia. Data are lacking to provide guidance regarding thresholds for prophylactic platelet transfusions in preterm neonates with severe thrombocytopenia.

Methods: In this multicenter trial, we randomly assigned infants born at less than 34 weeks of gestation in whom severe thrombocytopenia developed to receive a platelet transfusion at platelet-count thresholds of 50,000 per cubic millimeter (high-threshold group) or 25,000 per cubic millimeter (low-threshold group). Bleeding was documented prospectively with the use of a validated bleeding-assessment tool. The primary outcome was death or new major bleeding within 28 days after randomization.

Results: A total of 660 infants (median birth weight, 740 g; and median gestational age, 26.6 weeks) underwent randomization. In the high-threshold group, 90% of the infants (296 of 328 infants) received at least one platelet transfusion, as compared with 53% (177 of 331 infants) in the low-threshold group. A new major bleeding episode or death occurred in 26% of the infants (85 of 324) in the high-threshold group and in 19% (61 of 329) in the low-threshold group (odds ratio, 1.57; 95% confidence interval [CI], 1.06 to 2.32; P=0.02). There was no significant difference between the groups with respect to rates of serious adverse events (25% in the high-threshold group and 22% in the low-threshold group; odds ratio, 1.14; 95% CI, 0.78 to 1.67).

Conclusions: Among preterm infants with severe thrombocytopenia, those randomly assigned to receive platelet transfusions at a platelet-count threshold of 50,000 per cubic millimeter had a significantly higher rate of death or major bleeding within 28 days after randomization than those who received platelet transfusions at a platelet-count threshold of 25,000 per cubic millimeter. (Funded by the National Health Service Blood and Transplant Research and Development Committee and others; Current Controlled Trials number, ISRCTN87736839 .).
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http://dx.doi.org/10.1056/NEJMoa1807320DOI Listing
January 2019

Early treatment versus expectative management of patent ductus arteriosus in preterm infants: a multicentre, randomised, non-inferiority trial in Europe (BeNeDuctus trial).

BMC Pediatr 2018 08 4;18(1):262. Epub 2018 Aug 4.

Department of Paediatrics, Division of Neonatology, Radboud university medical centre Nijmegen, Radboud Institute for Health Sciences, Amalia Children's Hospital, Internal postal code 804, Geert Grooteplein Zuid 10, 6525, GA, Nijmegen, The Netherlands.

Background: Much controversy exists about the optimal management of a patent ductus arteriosus (PDA) in preterm infants, especially in those born at a gestational age (GA) less than 28 weeks. No causal relationship has been proven between a (haemodynamically significant) PDA and neonatal complications related to pulmonary hyperperfusion and/or systemic hypoperfusion. Although studies show conflicting results, a common understanding is that medical or surgical treatment of a PDA does not seem to reduce the risk of major neonatal morbidities and mortality. As the PDA might have closed spontaneously, treated children are potentially exposed to iatrogenic adverse effects. A conservative approach is gaining interest worldwide, although convincing evidence to support its use is lacking.

Methods: This multicentre, randomised, non-inferiority trial is conducted in neonatal intensive care units. The study population consists of preterm infants (GA < 28 weeks) with an echocardiographic-confirmed PDA with a transductal diameter > 1.5 mm. Early treatment (between 24 and 72 h postnatal age) with the cyclooxygenase inhibitor (COXi) ibuprofen (IBU) is compared with an expectative management (no intervention intended to close a PDA). The primary outcome is the composite of mortality, and/or necrotising enterocolitis (NEC) Bell stage ≥ IIa, and/or bronchopulmonary dysplasia (BPD) defined as the need for supplemental oxygen, all at a postmenstrual age (PMA) of 36 weeks. Secondary outcome parameters are short term sequelae of cardiovascular failure, comorbidity and adverse events assessed during hospitalization and long-term neurodevelopmental outcome assessed at a corrected age of 2 years. Consequences regarding health economics are evaluated by cost effectiveness analysis and budget impact analysis.

Discussion: As a conservative approach is gaining interest, we investigate whether in preterm infants, born at a GA less than 28 weeks, with a PDA an expectative management is non-inferior to early treatment with IBU regarding to the composite outcome of mortality and/or NEC and/or BPD at a PMA of 36 weeks.

Trial Registration: This trial is registered with the Dutch Trial Register NTR5479 (registered on 19 October 2015), the registry sponsored by the United States National Library of Medicine Clinicaltrials.gov NCT02884219 (registered May 2016) and the European Clinical Trials Database EudraCT 2017-001376-28 .
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http://dx.doi.org/10.1186/s12887-018-1215-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6090763PMC
August 2018

Optimal Target Range of Closed-Loop Inspired Oxygen Support in Preterm Infants: A Randomized Cross-Over Study.

J Pediatr 2018 06 21;197:36-41. Epub 2018 Mar 21.

Department of Neonatology, Emma Children's Hospital, Academic Medical Center Amsterdam, The Netherlands.

Objective: To investigate the effect of different pulse oximetry (SpO) target range settings during automated fraction of inspired oxygen control (A-FiO) on time spent within a clinically set SpO alarm range in oxygen-dependent infants on noninvasive respiratory support.

Study Design: Forty-one preterm infants (gestational age [median] 26 weeks, age [median] 21 days) on FiO >0.21 receiving noninvasive respiratory support were subjected to A-FiO using 3 SpO target ranges (86%-94%, 88%-92%, or 89%-91%) in random order for 24 hours each. Before switching to the next target range, SpO was manually controlled for 24 hours (washout period). The primary outcome was the time spent within the clinically set alarm limits of 86%-94%.

Results: The percent time within the 86%-94% SpO alarm range was similar for all 3 A-FiO target ranges (74%). Time spent in hyperoxemia was not significantly different between target ranges. However, the time spent in severe hypoxemia (SpO <80%) was significantly reduced during the narrowed target ranges of A-FiO (88%-92%; 1.9%, 89%-91%; 1.7%) compared with the wide target range (86%-94%; 3.4%, P < .001). There were no differences between the 88%-92% and 89-91% target range.

Conclusions: Narrowing the target range of A-FiO to the desired median ±2% is effective in reducing the time spent in hypoxemia, without increasing the risk of hyperoxemia.

Trial Registration: www.trialregister.nl: NTR4368.
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http://dx.doi.org/10.1016/j.jpeds.2018.01.077DOI Listing
June 2018

Systemic Hydrocortisone To Prevent Bronchopulmonary Dysplasia in preterm infants (the SToP-BPD study): statistical analysis plan.

Trials 2018 Mar 9;19(1):178. Epub 2018 Mar 9.

Department of Neonatology, Emma Children's Hospital, Academic Medical Centre, Room H3-145, PO Box 22700, 1100, DD, Amsterdam, The Netherlands.

Background: Bronchopulmonary dysplasia (BPD) is the most common complication of preterm birth with short-term and long-term adverse consequences. Although the glucocorticoid dexamethasone has been proven to be beneficial for the prevention of BPD, there are concerns about an increased risk of adverse neurodevelopmental outcome. Hydrocortisone has been suggested as an alternative therapy. The aim of the Systemic Hydrocortisone To Prevent Bronchopulmonary Dysplasia in preterm infants (SToP-BPD) trial is to assess the efficacy and safety of postnatal hydrocortisone administration for the reduction of death or BPD in ventilator-dependent preterm infants.

Methods/design: The SToP-BPD study is a multicentre, double-blind, placebo-controlled hydrocortisone trial in preterm infants at risk for BPD. After parental informed consent is obtained, ventilator-dependent infants are randomly allocated to hydrocortisone or placebo treatment during a 22-day period. The primary outcome measure is the composite outcome of death or BPD at 36 weeks postmenstrual age. Secondary outcomes are short-term effects on pulmonary condition and long-term neurodevelopmental sequelae assessed at 2 years corrected age. Complications of treatment, other serious adverse events and suspected unexpected serious adverse reactions are reported as safety outcomes. This pre-specified statistical analysis plan was written and submitted without knowledge of the unblinded data.

Trial Registration: Netherlands Trial Register, NTR2768 . Registered on 17 February 2011. EudraCT, 2010-023777-19. Registered on 2 November 2010.
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http://dx.doi.org/10.1186/s13063-018-2505-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5845134PMC
March 2018

High versus standard dose caffeine for apnoea: a systematic review.

Arch Dis Child Fetal Neonatal Ed 2018 Nov 7;103(6):F523-F529. Epub 2018 Feb 7.

Department of Neonatology, Emma Children's Hospital, Academic Medical Center, Amsterdam, Noord-Holland, The Netherlands.

Background: Placebo-controlled trials have shown that caffeine is highly effective in treating apnoea of prematurity and reduces the risk of bronchopulmonary dysplasia (BPD) and neurodevelopmental impairment (NDI).

Objective: To identify, appraise and summarise studies investigating the modulating effect of different caffeine dosages.

Methods: A systematic review identified all randomised controlled trials (RCTs) comparing a high versus a standard caffeine treatment regimen in infants with a gestational age <32 weeks, by searching the main electronic databases and abstracts of the Pediatric Academic Societies. Studies comparing caffeine to placebo or theophylline only were excluded. Primary outcomes were BPD and mortality at 36 weeks postmenstrual age. Secondary key-outcome was neurodevelopmental outcome at 12 and 24 months corrected age. Meta-analysis was performed using RevMan 5.3.

Results: Six RCTs including 620 infants were identified. Meta-analysis showed a significant decrease in BPD, the combined outcome BPD or mortality, and failure to extubate in infants allocated to a higher caffeine dose. No differences were found in mortality alone and NDI. The quality of the outcome measures were deemed low to very low according to the Grading of Recommendations Assessment, Development and Evaluation guidelines.

Conclusions: Although this review suggests that administering a higher dose of caffeine might enhance its beneficial effect on death or BPD, firm recommendations on the optimal caffeine dose cannot be given due to the low level of evidence. A large RCT is urgently needed to confirm or refute these findings and determine the optimal dose of caffeine.
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http://dx.doi.org/10.1136/archdischild-2017-313556DOI Listing
November 2018

Classifying Apnea of Prematurity by Transcutaneous Electromyography of the Diaphragm.

Neonatology 2018 1;113(2):140-145. Epub 2017 Dec 1.

Department of Neonatology, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands.

Background: Treatment of apnea is highly dependent on the type of apnea. Chest impedance (CI) has inaccuracies in monitoring respiration, which compromises accurate apnea classification. Electrical activity of the diaphragm measured by transcutaneous electromyography (EMG) is feasible in preterm infants and might improve the accuracy of apnea classification.

Objectives: To compare the accuracy of apnea classification based on diaphragmatic EMG (dEMG) and CI tracings in preterm infants.

Methods: Fifteen cases of central apnea, 5 of obstructive apnea, and 10 of mixed apnea were selected from recordings containing synchronized continuous tracings of respiratory inductive plethysmography (RIP), airway flow, heart rate (HR), oxygen saturation (SpO2), and breathing activity measured by dEMG and CI. Twenty-two assessors (neonatologists, pediatricians-in-training, and nurses) classified each apnea twice; once based on dEMG, HR, and SpO2 tracings, and once based on CI, HR, and SpO2. The assessors were blinded to the type of respiratory tracing (dEMG or CI) and to the RIP and flow tracings.

Results: In total 1,320 assessments were performed, and in 71.1% the apnea was classified correctly. Subgroup analysis based on respiratory tracing showed that 74.8% of the dEMG tracings were classified correctly compared to 67.3% of the CI tracings (p < 0.001). This improved apnea classification based on dEMG was present for central (86.7 vs. 80.3%, p < 0.02) and obstructive (56.4 vs. 32.7%, p < 0.001) apnea. The improved apnea classification based on dEMG tracing was independent of the type of assessor.

Conclusion: Transcutaneous dEMG improves the accuracy of apnea classification when compared to CI in preterm infants, making this technique a promising candidate for future monitoring systems.
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http://dx.doi.org/10.1159/000484081DOI Listing
September 2019

Ventilation in Preterm Infants and Lung Function at 8 Years.

N Engl J Med 2017 10;377(16):1600-1

Academic Medical Center, Amsterdam, the Netherlands

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http://dx.doi.org/10.1056/NEJMc1711170DOI Listing
October 2017

Late (≥ 7 days) inhalation corticosteroids to reduce bronchopulmonary dysplasia in preterm infants.

Cochrane Database Syst Rev 2017 08 24;8:CD002311. Epub 2017 Aug 24.

Department of Neonatology, Emma Children's Hospital AMC, University of Amsterdam, Meibergdreef 9, Amsterdam, Netherlands, 1105 AZ.

Background: Bronchopulmonary dysplasia (BPD), defined as oxygen dependence at 36 weeks postmenstrual age (PMA), remains an important complication of prematurity. Pulmonary inflammation plays a central role in the pathogenesis of BPD. Attenuating pulmonary inflammation with postnatal systemic corticosteroids reduces the incidence of BPD in preterm infants but may be associated with an increased risk of adverse neurodevelopmental outcomes. Local administration of corticosteroids via inhalation might be an effective and safe alternative.

Objectives: To determine if administration of inhalation corticosteroids after the first week of life until 36 weeks PMA to preterm infants at high risk of developing BPD is effective and safe in reducing the incidence of death and BPD as separate or combined outcomes.

Search Methods: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 4), MEDLINE via PubMed (1966 to 19 May 2017), Embase (1980 to 19 May 2017), and CINAHL (1982 to 19 May 2017). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials.

Selection Criteria: We included randomised controlled trials comparing inhalation corticosteroids, started ≥ 7 days postnatal age (PNA) but before 36 weeks PMA, to placebo in ventilated and non-ventilated infants at risk of BPD. We excluded trials investigating systemic corticosteroids versus inhalation corticosteroids.

Data Collection And Analysis: We collected data on participant characteristics, trial methodology, and inhalation regimens. The primary outcome was death or BPD at 36 weeks PMA. Secondary outcomes were the combined outcome death or BPD at 28 days PNA, the seperate outcomes of death and BPD at both 28 days PNA, and at 36 weeks PMA, and short-term respiratory outcomes, such as failure to extubate; total days of mechanical ventilation and oxygen use; and the need for systemic corticosteroids. We contacted the original trialists to verify the validity of extracted data and to provide missing data. We analysed all data using Review Manager 5. When possible, we performed meta-analysis using typical risk ratio (RR) for dichotomous outcomes and weighted mean difference (WMD) for continuous outcomes along with their 95% confidence intervals (CI). We analysed ventilated and non-ventilated participants separately.We used the GRADE approach to assess the quality of the evidence.

Main Results: We included eight trials randomising 232 preterm infants in this review. Inhalation corticosteroids did not reduce the separate or combined outcomes of death or BPD. The meta-analyses of the studies showed a reduced risk in favor of inhalation steroids regarding failure to extubate at seven days (typical RR (TRR) 0.80, 95% CI 0.66 to 0.98; 5 studies, 79 infants) and at the latest reported time point after treatment onset (TRR 0.60, 95% CI 0.45 to 0.80; 6 studies, 90 infants). However, both analyses showed increased statistical heterogeneity (I statistic 73% and 86%, respectively). Furthermore, inhalation steroids did not impact total duration of mechanical ventilation or oxygen dependency. There was a trend toward a reduction in the use of systemic corticosteroids in infants receiving inhalation corticosteroids (TRR 0.51, 95% CI 0.26 to 1.00; 4 studies, 74 infants; very low-quality evidence). There was a paucity of data on short- and long-term adverse effects. Our results should be interpreted with caution because the total number of randomised participants is relatively small, and most trials differed considerably in participant characteristics, inhalation therapy, and outcome definitions.

Authors' Conclusions: Based on the results of the currently available evidence, inhalation corticosteroids initiated at ≥ 7 days of life for preterm infants at high risk of developing BPD cannot be recommended at this point in time. More and larger randomised, placebo-controlled trials are needed to establish the efficacy and safety of inhalation corticosteroids.
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http://dx.doi.org/10.1002/14651858.CD002311.pub4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483527PMC
August 2017

Restricted Ventilation Associated with Reduced Neurodevelopmental Impairment in Preterm Infants.

Neonatology 2017 10;112(2):172-179. Epub 2017 Jun 10.

Department of Neonatology, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands.

Background And Objective: Restrictive use of invasive mechanical ventilation (IMV) in preterm infants reduces the risk of bronchopulmonary dysplasia (BPD). Our objective was to determine its effect on neurodevelopmental impairment (NDI) at 24 months' corrected age (CA).

Methods: This retrospective single-center cohort study included all patients with a gestational age <30 weeks born in 2004/2005 (epoch 1) and 2010/2011 (epoch 2). In epoch 2, we introduced a policy of restriction on IMV and liberalized the use of respiratory stimulants in the delivery room and neonatal intensive care. Data on patient characteristics, respiratory management, short-term outcomes, mortality, BPD, and NDI at 24 months' CA were collected.

Results: Four hundred and four preterm infants were included. Compared to those in epoch 1, infants in epoch 2 were less likely to be intubated and the duration of IMV was shorter. Other noninvasive adjuvant therapies such as caffeine, doxapram, and nasal ventilation were more often used during epoch 2. There was a trend to less BPD in epoch 2 compared to epoch 1 (17 vs. 23%, adjusted OR = 0.75, 95% CI: 0.48, 1.16). Mortality did not change over time. The combined outcome death or NDI at 24 months' CA was significantly lower in epoch 2 compared to epoch 1 (24.7 vs. 33.9%, adjusted OR = 0.71, 95% CI: 0.53, 0.97).

Conclusions: Restricted use of IMV is feasible in preterm infants and might be associated with a reduced risk of the combined outcome death or NDI at 24 months' CA. Larger studies are needed to confirm these findings.
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http://dx.doi.org/10.1159/000471841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5637296PMC
May 2018

Systemic corticosteroid regimens for prevention of bronchopulmonary dysplasia in preterm infants.

Cochrane Database Syst Rev 2017 01 31;1:CD010941. Epub 2017 Jan 31.

Department of Neonatology, Emma Children's Hospital AMC, University of Amsterdam, Meibergdreef 9, Amsterdam, Netherlands, 1105 AZ.

Background: Cochrane systematic reviews show that systemic postnatal corticosteroids reduce the risk of bronchopulmonary dysplasia (BPD) in preterm infants. However, corticosteroids have also been associated with an increased risk of neurodevelopmental impairment. It is unknown whether these beneficial and adverse effects are modulated by differences in corticosteroid treatment regimens.

Objectives: To assess the effects of different corticosteroid treatment regimens on mortality, pulmonary morbidity, and neurodevelopmental outcome in very low birth weight (VLBW) infants.

Search Methods: We used the standard search strategy of the Cochrane Neonatal Review group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 2) in the Cochrane Library (searched 21 March 2016), MEDLINE via PubMed (1966 to 21 March 2016), Embase (1980 to 21 March 2016), and CINAHL (1982 to 21 March 2016). We also searched clinical trials' databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials.

Selection Criteria: Randomized controlled trials (RCTs) comparing two or more different treatment regimens of systemic postnatal corticosteroids in preterm infants at risk for BPD, as defined by the original trialists. Studies investigating one treatment regimen of systemic corticosteroids to a placebo or studies using inhalation corticosteroids were excluded.

Data Collection And Analysis: Two authors independently assessed eligibility and quality of trials and extracted data on study design, participant characteristics and the relevant outcomes. We asked the original investigators to verify if data extraction was correct and, if possible, to provide any missing data. The primary outcomes to be assessed were: mortality at 36 weeks' postmenstrual age (PMA) or at hospital discharge; BPD defined as oxygen dependency at 36 weeks' PMA; long-term neurodevelopmental sequelae, including cerebral palsy, measured by the Bayley Mental Developmental Index (MDI); and blindness or poor vision. Secondary outcomes were: duration of mechanical ventilation and failure to extubate at day 3 and 7 after initiating therapy; rescue treatment with corticosteroids outside the study period; and the incidence of hypertension, sepsis and hyperglycemia during hospitalizations. Data were analyzed using Review Manager 5 (RevMan 5). We used the GRADE approach to assess the quality of evidence.

Main Results: Fourteen studies were included in this review. Only RCTs investigating dexamethasone were identified. Eight studies enrolling a total of 303 participants investigated the cumulative dosage administered; three studies contrasted a high versus a moderate and five studies a moderate versus a low cumulative dexamethasone dose.Analysis of the studies investigating a moderate dexamethasone dose versus a high-dosage regimen showed an increased risk of BPD (typical risk ratio (RR) 1.50, 95% confidence interval (CI) 1.01 to 2.22; typical risk difference (RD) 0.26, 95% CI 0.03 to 0.49; number needed to treat for an additional harmful outcome (NNTH) 4, 95% CI 1.9 to 23.3; I² = 0%, 2 studies, 55 infants) as well as an increased risk of abnormal neurodevelopmental outcome (typical RR 8.33, 95% CI 1.63 to 42.48; RD 0.30, 95% CI 0.14 to 0.46; NNTH 4, 95% CI 2.2 to 7.3; I² = 68%, 2 studies, 74 infants) when using a moderate cumulative-dosage regimen. The composite outcomes of death or BPD and death or abnormal neurodevelopmental outcome showed similar results although the former only reached borderline significance.There were no differences in outcomes between a moderate- and a low-dosage regimen.Four other studies enrolling 762 infants investigated early initiation of dexamethasone therapy versus a moderately early or delayed initiation and showed no significant differences in the primary outcomes. The two RCTs investigating a continuous versus a pulse dexamethasone regimen showed an increased risk of the combined outcome death or BPD when using the pulse therapy. Finally, two trials investigating a standard regimen versus a participant-individualized course of dexamethasone showed no difference in the primary outcome and long-term neurodevelopmental outcomes.The quality of evidence for all comparisons discussed above was assessed as low or very low, because the validity of all comparisons is hampered by small samples of randomized infants, heterogeneity in study population and design, non-protocolized use of 'rescue' corticosteroids and lack of long-term neurodevelopmental data in most studies.

Authors' Conclusions: Despite the fact that some studies reported a modulating effect of treatment regimens in favor of higher-dosage regimens on the incidence of BPD and neurodevelopmental impairment, recommendations on the optimal type of corticosteroid, the optimal dosage, or the optimal timing of initiation for the prevention of BPD in preterm infants cannot be made based on current level of evidence. A well-designed large RCT is urgently needed to establish the optimal systemic postnatal corticosteroid dosage regimen.
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http://dx.doi.org/10.1002/14651858.CD010941.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6464844PMC
January 2017

Increased incidence of necrotizing enterocolitis in the Netherlands after implementation of the new Dutch guideline for active treatment in extremely preterm infants: Results from three academic referral centers.

J Pediatr Surg 2017 Feb 14;52(2):273-276. Epub 2016 Nov 14.

Department of Pediatric Surgery, Pediatric Surgical Center Amsterdam, Amsterdam, The Netherlands.

Introduction: Necrotizing enterocolitis (NEC) is a severe inflammatory disease, mostly occurring in preterm infants. The Dutch guidelines for active treatment of extremely preterm infants changed in 2006 from 26+0 to 25+0weeks of gestation, and in 2010 to 24+0 of gestation. We aimed to gain insight into the incidence, clinical outcomes and treatment strategies, in three academic referral centers in the Netherlands over the last nine years.

Methods: We performed a multicenter retrospective cohort study of all patients with NEC (Bell stage ≥2a) in three academic referral centers diagnosed between 2005 and 2013. Outcome measures consisted of incidence, changes in clinical presentation, treatment strategies and mortality.

Results: Between 2005 and 2013 14,161 children were admitted to the neonatal intensive care unit in the three centers. The overall percentage of children born at a gestational age of 24weeks and 25weeks increased with 1.7% after the introduction of the guidelines in 2006 and 2010. The incidence of NEC increased significantly (period 2005-2007: 2.1%; period 2008-2010 3.9%; period 2011-2013: 3.4%; P=0.001). We observed a significant decrease of peritoneal drainages (↓16%; P=0.001) and a decrease of laparotomies (↓24%; P=0.002). The mortality rate (33% in 2011-2013) remained unchanged.

Conclusion: The incidence of NEC significantly increased in the last nine years. The increase in incidence of NEC seemed to be related to an increase in infants born at a gestational age of 24 and 25weeks. The percentage of patients needing surgery decreased, while 30-day mortality did not change.

Level Of Evidence: Level IV.
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http://dx.doi.org/10.1016/j.jpedsurg.2016.11.024DOI Listing
February 2017

Doxapram Treatment for Apnea of Prematurity: A Systematic Review.

Neonatology 2017 20;111(2):162-171. Epub 2016 Oct 20.

Department of Neonatology, Emma Childrens' Hospital AMC, Amsterdam, The Netherlands.

Background: Apnea of prematurity (AOP) is a common complication of preterm birth, for which caffeine is the first treatment of choice. In case of persistent AOP, doxapram has been advocated as an additional therapy.

Objective: To identify and appraise all existing evidence regarding efficacy and safety of doxapram use for AOP in infants born before 34 weeks of gestational age.

Methods: All studies reporting on doxapram use for AOP were identified by searching electronic databases, references from relevant studies, and abstracts from the Societies for Pediatric Research. Two reviewers independently assessed study eligibility and quality, and extracted data on study design, patient characteristics, efficacy and safety outcomes.

Results: The randomized controlled trials showed less apnea during doxapram treatment when compared to placebo, but no difference in treatment effect when compared to theophylline. No serious adverse effects were reported. We identified 28 observational studies consisting mainly of cohort studies and case series (n = 1,994). There was considerable heterogeneity in study design and quality. Most studies reported a positive effect of doxapram on apnea rate. A few studies reported on long-term outcomes with conflicting results. A range of possible doxapram-related short-term adverse effects were reported, sometimes associated with the use of higher doses.

Conclusion: Based on the limited number of studies and level of evidence, no firm conclusions on the efficacy and safety of doxapram in preterm infants can be drawn. For this reason, routine use cannot be recommended. A large multicenter randomized controlled trial is urgently needed to provide more conclusive evidence.
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http://dx.doi.org/10.1159/000448941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5296887PMC
December 2017

Prophylactic low-dose hydrocortisone treatment increases the rate of survival without bronchopulmonary dysplasia in extremely preterm infants.

Evid Based Med 2016 10 11;21(5):177. Epub 2016 Aug 11.

Department of Neomatology, Emma Children's Hospital Academic Medical Center, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1136/ebmed-2016-110505DOI Listing
October 2016